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HSP90 Inhibition Leads to Degradation of the TYK2 Kinase and Apoptotic Cell Death in T-Cell Acute Lymphoblastic Leukemia

Akahane, Koshi and Sanda, Takaomi and Mansour, Marc R. and Radimerski, Thomas and Weinstock, David M. and Letai, Anthony and Look, Thomas (2016) HSP90 Inhibition Leads to Degradation of the TYK2 Kinase and Apoptotic Cell Death in T-Cell Acute Lymphoblastic Leukemia. Leukemia, 30 (1). pp. 219-228. ISSN 1476-5551; 0887-6924

Abstract

Abstract
We have previously shown that TYK2 tyrosine kinase signaling through its downstream effector phospho-STAT1 (p-STAT1) acts to upregulate BCL2, which mediates the aberrant survival of T-cell acute lymphoblastic leukemia (T-ALL) cells. In this study, we demonstrate that pharmacological inhibition of heat shock protein 90 (HSP90) with a small-molecule inhibitor, NVP-AUY922 (AUY922), leads to the rapid degradation of TYK2 and apoptosis in T-ALL cells. STAT1 protein expression levels are unaffected by AUY922 treatment, but p-STAT1 (Tyr 701) levels rapidly become undetectable, consistent with a block in signaling downstream of TYK2. BCL2 expression is downregulated after AUY922 treatment, and although this effect is necessary for AUY922-induced apoptosis, it is not sufficient because many T-ALL cell lines are resistant to BCL2 inhibition by ABT-199. Our study reveals that unlike ABT-199, AUY922 also upregulates the pro-apoptotic proteins BIM and BAD, and that the synergistic combination of downregulation of BCL2 and upregulation of BH3-only proteins explains the potent pro-apoptotic activity of AUY922 in T-ALL cells.

Significance
Despite advances in the therapy for patients with T-ALL, nearly 25% of children and greater than 50% of adults still succumb to this disease, indicating that further therapeutic improvements are urgently needed. Our study shows that pharmacological inhibition of HSP90 by a small-molecule inhibitor currently in clinical trials efficiently induces apoptosis in T-ALL cells through the combined effects of blocking the TYK2-STAT1-BCL2 pro-survival pathway and simultaneously upregulating the BIM and BAD pro-apoptotic BH3-only proteins.

Item Type: Article
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45
URI: https://oak.novartis.com/id/eprint/24542

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